The significance of type I interferons (IFN-alpha/beta) in biology and medicine renders research on their activities continuously relevant to our understanding of normal and abnormal (auto) immune responses. This relevance is bolstered by discoveries that unambiguously establish IFN-alpha/beta, among the multitude of cytokines, as dominant in defining qualitative and quantitative characteristics of innate and adaptive immune processes. Recent advances elucidating the biology of these key cytokines include better definition of their complex signaling pathways, determination of their importance in modifying the effects of other cytokines, the role of Toll-like receptors in their induction, their major cellular producers, and their broad and diverse impact on both cellular and humoral immune responses. Consequently, the role of IFN-alpha/beta in the pathogenesis of autoimmunity remains at the forefront of scientific inquiry and has begun to illuminate the mechanisms by which these molecules promote or inhibit systemic and organ-specific autoimmune diseases.

The role of specialized follicular helper T (TFH) cells in the germinal center has become well recognized, but it is less clear how effector T cells govern the extrafollicular response, the dominant pathway of high-affinity, isotype-switched autoantibody production in the MRL/MpJ-Faslpr (MRLlpr) mouse model of lupus. MRLlpr mice lacking the Icos gene have impaired extrafollicular differentiation of immunoglobulin (Ig) G+ plasma cells accompanied by defects in CXC chemokine receptor (CXCR) 4 expression, interleukin (IL) 21 secretion, and B cell helper function in CD4 T cells. These phenotypes reflect the selective loss of a population of T cells marked by down-regulation of P-selectin glycoprotein ligand 1 (PSGL-1; also known as CD162). PSGL-1lo T cells from MRLlpr mice express CXCR4, localize to extrafollicular sites, and uniquely mediate IgG production through IL-21 and CD40L. In other autoimmune strains, PSGL-1lo T cells are also abundant but may exhibit either a follicular or extrafollicular phenotype. Our findings define an anatomically distinct extrafollicular population of cells that regulates plasma cell differentiation in chronic autoimmunity, indicating that specialized humoral effector T cells akin to TFH cells can occur outside the follicle.

Efforts to understand autoimmunity have been pursued relentlessly for several decades. It has become apparent that the immune system evolved multiple mechanisms for controlling self-reactivity, and defects in one or more of these mechanisms can lead to breakdown of tolerance. Among the multitude of lesions associated with disease, the most common appear to affect peripheral rather than central tolerance. The initial trigger for both systemic and organ-specific autoimmune disorders likely involves recognition of self or foreign molecules, especially nucleic acids, by innate sensors. This recognition, in turn, triggers inflammatory responses and engagement of previously quiescent autoreactive T and B cells. Here, we summarize the most prominent autoimmune pathways and identify key issues that require resolution to fully understand pathogenic autoimmunity.

Indirect evidence suggests that type-I interferons (IFN-α/β) play a significant role in the pathogenesis of lupus. To directly examine the contribution of these pleiotropic molecules, we created congenic NZB mice lacking the α-chain of IFN-α/βR, the common receptor for the multiple IFN-α/β species. Compared with littermate controls, homozygous IFN-α/βR-deleted NZB mice had significantly reduced anti-erythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease, and mortality. These reductions were intermediate in the heterozygous-deleted mice. The disease-ameliorating effects were accompanied by reductions in splenomegaly and in several immune cell subsets, including B-1 cells, the major producers of anti-erythrocyte autoantibodies. Decreases of B and T cell proliferation in vitro and in vivo, and of dendritic cell maturation and T cell stimulatory activity in vitro were also detected. Absence of signaling through the IFN-α/βR, however, did not affect increased basal levels of the IFN-responsive p202 phosphoprotein, encoded by a polymorphic variant of the Ifi202 gene associated with the Nba2 predisposing locus in NZB mice. The data indicate that type-I IFNs are important mediators in the pathogenesis of murine lupus, and that reducing their activity in the human counterpart may be beneficial.

We formulate a two-phase paradigm of autoimmunity associated with systemic lupus erythematosus, the archetypal autoimmune disease. The initial Toll-like receptor (TLR)-independent phase is mediated by dendritic cell uptake of apoptotic cell debris and associated nucleic acids, whereas the subsequent TLR-dependent phase serves an amplification function and is mediated by uptake of TLR ligands derived from self-antigens (principally nucleic acids) complexed with autoantibodies. Both phases depend on elaboration of type I interferons (IFNs), and therapeutic interruption of induction or activity of these cytokines in predisposed individuals might have a substantial mitigating effect in lupus and other autoimmune diseases.

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Su ibity to systec lupus erythematosus has been unequivocally e d to be an inherited trai, but the exact genes and how they confer susceptibility n largely unknown. In this study of (NZB x NZW)F2 inte mice, we used linkage analysis ofmarkers covering >90% ofthe automal genome and idenified eit ptl ld chomosomes 17,(4)(5)(6)(7)18,1,11, pectively) ated with antichromatin autoantibody production, gm nphris, and/or it. Only one locus, the major his patibt complx, was linked to all three traits. Two other loci were ed with both glomerulonephitis and mortalt, whereas the remaining loci were linked to one of the above traits. Two adial loci (Sbwl and -2) that conibut to p m were also iden- Among the murine lupus strains, the (NZB x NZW)F1 (BWF1) hybrid has clinical features most closely resembling human SLE with markedly accelerated disease compared with parental strains and a striking female predilection (2). Conventional genetic studies indicate that each of the parental strains contributes at least one or two genes (3, 4), one of which is linked to the MHC locus, with heterozygosity (H-2dz) conferring maximal susceptibility (5,6).The recent identification of thousands of polymorphic dinucleotide repeats (microsatellites) that can be used to create dense linkage maps between inbred strains (7, 8) has made it feasible to systematically search the entire mouse genome for susceptibility gene loci. We have used this approach to map the genes predisposing to early disease in the BWF1 hybrid and report the identification of several loci predisposing to mortality, glomerulonephritis (GN), antichromatin antibody production, and splenomegaly.MATERIALS AND METHODS Mice. NZB/BlScr, NZW/LacScr, BWF1, and (NZB x NZW)F2 (BWF2) intercross mice were bred and maintained in our animal colony. Female mice from 6 mo of age were examined daily for disease, bled monthly for sera, and sacrificed at either 1 yr of age or earlier if moribund.Phenotyping of Mice. Autopsies and histologic examinations were done as described (9). Severity of GN was graded from 0 to 4+ (9), and mice were considered to have severe GN ifthey were 4+ at 12 mo or .3+ ifmice eitherdied earlier or had anasarca. Survival comparisons and cumulative antichromatin antibody levels were analyzed with the generalized Wilcoxon test. Comparisons of spleen size were done with the Mann-Whitney U test for small sample sizes and the Student's t test for larger samples. ELISA for chromatin was done as described (10). For linkage analysis, BWF2 mice with antichromatin antibody levels of OD > 0.5 by 11 mo were considered positive.Cbromosoma Markers and Genotyping of Mice. Chromosomal markers consisted of simple-sequence-length polymorphisms (SSLPs) identified by PCR (refs. 7,8

Although natural Abs (NAbs) are present from birth, little is known about what drives their selection and whether they have housekeeping functions. The prototypic T15-NAb, first identified because of its protective role in infection, is representative of a special type of NAb response that specifically recognizes and forms complexes with apoptotic cells and which promotes cell-corpse engulfment by phagocytes. We now show that this T15-NAb IgM-mediated clearance process is dependent on the recruitment of C1q and mannose-binding lectin, which have known immune modulatory activities that also provide “eat me” signals for enhancing phagocytosis. Further investigation revealed that the addition of T15-NAb significantly suppressed in vitro LPS-induced TNF-α and IL-6 secretion by the macrophage-like cell line, RAW264.7, as well as TLR3-, TLR4-, TLR7-, and TLR9-induced maturation and secretion of a range of proinflammatory cytokines and chemokines by bone marrow-derived conventional dendritic cells. Significantly, high doses of this B-1 cell produced NAb also suppressed in vivo TLR-induced proinflammatory responses. Although infusions of apoptotic cells also suppressed such in vivo inflammatory responses and this effect was associated with the induction of high levels of IgM antiapoptotic cell Abs, apoptotic cell treatment was not effective at suppressing such TLR responses in B cell-deficient mice. Moreover, infusions of T15-NAb also efficiently inhibited both collagen-induced arthritis and anti-collagen II Ab-mediated arthritis. These studies identify and characterize a previously unknown regulatory circuit by which a NAb product of innate-like B cells aids homeostasis by control of fundamental inflammatory pathways.